Cystic fibrosis (CF) is the most common life-shortening genetic disease in the United States and Northern Europe, affecting approximately 30,000 individuals in the United States (Cunningham, J. C. et al., “An Introduction to Cystic Fibrosis for Patients and Families,” 5th ed., Bethesda: Cystic Fibrosis Foundation (2003)) and a similar number of individuals in Western Europe. The genetic defect in this autosomal recessive disease is a mutation in the CF transmembrane conductance regulator (CFTR) gene, which codes for a chloride-channel protein (Collins, F. S., “Cystic Fibrosis Molecular Biology and Therapeutic Implications,” Science 256:774-779 (1992)). Persons with CF typically suffer from chronic endobronchial infections, sinusitis, and malabsorption due to pancreatic insufficiency, increased salt loss in sweat, obstructive hepatobiliary disease, and reduced fertility (FitzSimmons, S. C., “The Changing Epidemiology of Cystic Fibrosis,” J Pediatr 122:1-9 (1993)). Respiratory disease is a major cause of morbidity and accounts for 90% of mortality in persons with CF (Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report, Bethesda, Md.: Cystic Fibrosis Foundation, (2004); Davis, P. B. et al., “Cystic fibrosis,” Amer J. Respir Crit Care Med 154 (5):1229-56 (1996)). Lung function (measured as forced expiratory volume at 1 second (FEV1% predicted) is a significant predictor of survival in CF. Two-year survival for a given population of persons with CF is reduced 2-fold with each 10% reduction in FEV1% predicted, and persons with FEV1 below 30% of predicted have a 2-year survival below 50% (Kerem, E. et al., “Prediction of Mortality in Patients with Cystic Fibrosis,” N Engl J Med 326:1187-1191 (1992)). Rates of lung function loss vary both between individuals and over time for a given individual. Retrospective longitudinal analyses show rates of decline ranging from less than 2% of FEV1% predicted per year to greater than 9% FEV1% predicted per year, with overall rate of decline strongly associated with age of death (Corey, M. et al., “Longitudinal Analysis of Pulmonary Function Decline in Patients with Cystic Fibrosis,” J Pediatr 131 (6):809-1 (1997)).
CF patients suffer from thickened mucus caused by perturbed epithelial ion transport that impairs lung host defenses, resulting in increased susceptibility to early endobronchial infections with Staphylococcus aureus, Haemophilus influenzae, and P. aeruginosa. By adolescence, a majority of persons with CF have P. aeruginosa present in their sputum (Cystic Fibrosis Foundation Patient Registry 2003 Annual Data Report (2004)). Chronic endobronchial infections, particularly with P. aeruginosa, provoke a persistent inflammatory response in the airway that accelerates progressive obstructive disease characterized by diffuse bronchiectasis (Davis, P. B. et al. (1996), supra; Winnie, G. B. et al., “Respiratory Tract Colonization with Pseudomonas aeruginosa in Cystic Fibrosis: Correlations Between Anti-Pseudomonas aeruginosa Antibody Levels And Pulmonary Function,” Pediatr Pulmonol 10:92-100 (1991); Ballman, M. et al. “Long Term Follow Up of Changes in FEV1 and Treatment Intensity During Pseudomonas Aeruginosa Colonisation in Patients with Cystic Fibrosis,” Thorax 53:732-737 (1998); Pamukcu, A. et al., “Effects of Pseudomonas aeruginosa Colonization on Lung Function and Anthropometric Variables in Children with Cystic Fibrosis,” Pediatr Pulmonol 19:10-15 (1995)). A link between acquisition of chronic endobronchial P. aeruginosa infection, lung inflammation, loss of lung function, and ultimate death is suggested by significantly decreased survival associated with chronic P. aeruginosa infection (Henry, R. L. et al., “Mucoid Pseudomonas aeruginosa is a Marker of Poor Survival in Cystic Fibrosis,” Pediatr Pulmonol 12 (3):158-61 (1992)), and by the significant association of early acquisition of chronic P. aeruginosa infection and childhood mortality (Demko, C. A. et al., “Gender Differences in Cystic Fibrosis: Pseudomonas aeruginosa Infection,” J Clin Epidemiol 48:1041-1049 (1995)). Chronic Therapies that either suppress bacterial loads in the lung (MacLusky, I. B. et al, “Long-term Effects of Inhaled Tobramycin in Patients with Cystic Fibrosis Colonized with Pseudomonas aeruginosa,” Pediatr Pulmonol 7 (1):42-8 (1989)) or suppress resulting inflammation (Konstan, M. W. et “Effect of high-dose Ibuprofen in Patients with Cystic Fibrosis,” N Engl J Med 332 (13):848-54 (1995)) have been shown to reduce rates of lung function decline in infected patients.
Historically, the standard therapy for P. aeruginosa endobronchial infections was 14 to 21 days of parenteral antipseudomonal antibiotics, typically including an aminoglycoside. However, parenteral aminoglycosides, as highly polar agents, penetrate poorly into the endobronchial space. To obtain adequate drug concentrations at the site of infection with parenteral administration, serum levels approaching those associated with nephro-, vestibule-, and oto-toxicity are required (“American Academy of Otolaryngology. Guide for the evaluation of hearing handicap,” JAMA 241 (19):2055-9 (1979); Brummett, R. E., “Drug-induced ototoxicity,” Drugs 19:412-28 (1980)).
Inhalation administration of aminoglycosides offers an attractive alternative, delivering high concentrations of antibiotic directly to the site of infection in the endobronchial space while minimizing systemic bioavailability (Touw, D. J. et al., “Inhalation of Antibiotics in Cystic Fibrosis,” Eur Respir J 8:1594-604 (1995); Rosenfeld, M. et al., “Aerosolized Antibiotics for Bacterial Lower Airway Infections: Principles, Efficacy, and Pitfalls,” Clinical Pulmonary Medicine 4 (2):101-12 (1997)).
The current standard of treatment of P. aeruginosa infections in CF patients is TOBI® tobramycin solution for inhalation, a preservative-free, stable, and convenient formulation of tobramycin (60 mg/mL tobramycin in 5 mL of ¼ normal saline) for administration via jet nebulizer, developed by PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.). The combination of a 5 mL BID TOBI dose (300 mg tobramycin) and the PARI LC PLUS/PulmoAide compressor delivery system was approved by the FDA under NDA 50-753, December 1997, as a chronic intermittent therapy for the management of P. aeruginosa in CF patients, and remains the industry standard for this purpose. The process of inhalation of the commercially available 300 mg TOBI dose can take 20 minutes per dose with additional time required for set-up and nebulizer cleaning. The aerosol administration of a 5 ml dose of a formulation containing 300 mg of tobramycin in quarter normal saline for the suppression of P. aeruginosa in the endobronchial space of a patient is also disclosed in U.S. Pat. No. 5,508,269, the disclosure of which is incorporated herein in its entirety by this reference.
Tobramycin is an aminoglycoside antibiotic produced by the actinomycete, Streptomyces tenebrarius. Low concentrations of tobramycin (<4 μg/mL) are effective in inhibiting the growth of many Gram-negative bacteria and under certain conditions may be bactericidal (Neu, H. C., “Tobramycin: an overview,” J Infect Dis 134: Suppl: S3-19 (1976)). Tobramycin is poorly absorbed across mucosal surfaces, conventionally necessitating parenteral administration. In addition, tobramycin activity is inhibited by purulent sputum: high concentrations of divalent cations, acidic conditions, increased ionic strength and macromolecules that bind the drug all inhibit tobramycin in this environment. It is estimated that 5 to 10 times higher concentrations of tobramycin are required in the sputum to overcome these inhibitory effects (Levy, J. et al., “Bioactivity of Gentamicin in Purulent Sputum from Patients with Cystic Fibrosis or Bronchiectasis: Comparison with Activity in Serum,” J Infect Dis 148 (6): 1069-76 (1983)).
The effectiveness of delivery of the poorly absorbed antibiotic tobramycin to the airway by the aerosol route of cystic fibrosis (CF) patients has been well documented. Much of this work has been done toward treatment of chronic lung infections with P. aeruginosa in cystic fibrosis (CF) patients. For example, a multicenter, double blind, placebo-controlled, crossover trial of 600 mg tid of aerosolized tobramycin for endobronchial infections due to P. aeruginosa in 71 CF patients demonstrated a significant reduction in sputum density of this pathogen as well as improved spirometry in the treatment group. Emergence of P. aeruginosa strains highly resistant to tobramycin (defined as MIC ≧128 μg/mL) was comparable in the placebo and treatment groups. The presence in the sputum of Gram-negative organisms other than P. aeruginosa intrinsically resistant to tobramycin occurred with equal frequency during administration of tobramycin or placebo (Ramsey, B. et al., “Response to Letter to the Editor: Aerosolized Tobramycin in Patients with Cystic Fibrosis,” N Engl J Med 329:1660 (1993)).
Although this regimen was found to be both safe and efficacious, it is costly and inconvenient. A survey of the MICs for P. aeruginosa isolates from initial sputum cultures for patients at the Children's Hospital CF Center, Seattle, Wash., in 1993 found that 90% of isolates had MICs ≦16 μg/mL and 98% of all isolates had MICs ≦128 μg/mL. This survey suggested that achieving a sputum tobramycin concentration of 128 μg/mL should effectively treat endobronchial infections in CF patients (Levy, J. et al., “Bioactivity of Gentamicin in Purulent Sputum from Patients with Cystic Fibrosis or Bronchiectasis: Comparison with Activity in Serum,” J Infect Dis 148 (6):1069-76 (1983)).
A randomized, crossover study compared the ability of several nebulizers to deliver tobramycin by measuring peak sputum tobramycin concentrations in samples collected ten minutes after completion of the aerosol dose. This study administered TOBI® tobramycin solution for inhalation, PathoGenesis Corporation, Seattle, Wash. (now Chiron Corporation, Emeryville, Calif.), containing 60 mg/mL tobramycin in 5 mL one quarter (¼) normal saline, using the PARI® LC jet nebulizer, PARI Respiratory Equipment, Inc., Richmond, Va. This delivery system was shown to deliver a mean peak sputum tobramycin concentration of 678.8 μg/g (s.d. 661.0 μg/g), and a median peak sputum concentration of 433.0 μg/g. Only 13% of patients had sputum levels ≦128 μg/g; 87% of patients achieved sputum levels of ≧128 μg/g (Eisenberg, J. et al., “A Comparison of Peak Sputum Tobramycin Concentration in Patients With Cystic Fibrosis Using Jet and Ultrasonic Nebulizer Systems. Aerosolized Tobramycin Study Group,” Chest 111 (4):955-962 (1997)). Recently, the PARI® LC jet nebulizer has been modified with the addition of one-way flow valves, and renamed the PARI® LC PLUS. The one-way valves in the PARI® LC PLUS have been described as permitting the delivery of more drug than the PARI® LC jet nebulizer, while decreasing the potential for accidental spillage and allowing for the use of an expiratory filter. Experience has shown that mean peak sputum tobramycin concentrations achieved using the PARI LC PLUS jet nebulizer are significantly higher than those, using the PARI® LC jet nebulizer as described in Eisenberg et al. (1997), supra.
In addition to the foregoing, two placebo-controlled, multicenter, randomized, double blind clinical trials of intermittent administration of inhaled liquid aerosol tobramycin in cystic fibrosis patients with P. aeruginosa infection were reported in Ramsey, B. W. et al., “Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.” N. Engl. J. Med 340 (1):23-30 (1999). In these studies, five hundred twenty subjects were randomized to receive either 300 mg inhaled tobramycin or placebo twice daily for 28 days followed by 28 days off study drug. Subjects continued on treatment or placebo for three “on-off” cycles for a total of 24 weeks. Efficacy variables included sputum P. aeruginosa density. Tobramycin-treated patients had an average 0.8 log10 decrease in P. aeruginosa density from Week 0 to Week 20, compared with a 0.3 log10 increase in placebo-treated patients (P<0.001). Tobramycin-treated patients had an average 1.9 log10 decrease in P. aeruginosa density from Week 0 to Week 4, compared with no change in placebo-treated patients (P<0.001).
U.S. Pat. No. 6,890,907 and United States Published Patent Application 2003/0143162 A1 disclose that patients suffering from an endobronchial infection can be effectively treated by administering to the patient for inhalation a dose of 4.0 ml, or less, of a nebulized liquid aerosol formulation comprising from about 60 to about 200 mg/ml of an aminoglycoside antibiotic, such as tobramycin, in a physiologically acceptable carrier, in a time period of less than about 10 minutes. The more efficient administration of the aminoglycoside formulation permits substantially smaller volumes of liquid aminoglycoside than the conventional administration regime to be administered in substantially shorter periods of time, thereby reducing the costs of administration and drug waste. Moreover, the formulations were shown to contain a minimal yet efficacious amount of aminoglycoside formulated in a relatively small volume of a physiologically acceptable solution, thereby reducing irritation of the lungs after inhalation of the aminoglycoside formulation.
In addition to inhaled antibiotics such as the commercially available TOBI® product, a variety of other chronic therapies are routinely prescribed to reduce the destructive cycles of obstruction, infection, and inflammation in the CF lung. Aggressive Airway Clearance Therapy (Reisman, J. J. et al., “Role of conventional physiotherapy in cystic fibrosis,” J Pediatr 113 (4):632-6 (1988)), inhaled bronchodilators (Konig P et al., “Short-term and Long-term Effects of Albuterol Aerosol Therapy in Cystic Fibrosis: A Preliminary Report,” Pediatr Pulmonol 20 (4):205-14 (1995)), and mucolytics such as recombinant human dornase alpha (rhDNase; Fuchs, H. J. et al., “Effect of Aerosolized Recombinant Human DNase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis. The Pulmozyme Study Group,” N Engl J Med 331 (10):637-42 (1994)) are all prescribed chronically, creating a potential for significant treatment burden for persons with CF. It has been shown that adherence to therapies is a significant problem for persons with CF (Conway, S. P. et al., “Compliance with treatment in adult patients with cystic fibrosis,” Thorax 51 (1):29-33 (1996)) and that lack of compliance can vary by specific treatment (Abbott J et al., “Treatment Compliance in Adults with Cystic Fibrosis,” Thorax 49 (2):115-20 (1994)).
As described above, the commercially available TOBI® liquid aerosol tobramycin solution for inhalation has proven to be highly effective in treating P. aeruginosa infections in CF patients. Given the treatment burden and adherence challenges associated with preservation of lung function in persons with CF, improvements in existing therapies that reduce treatment administration time or increase convenience of treatment for patients will facilitate patient adherence and resulting therapeutic efficacy. Accordingly, there is a need for new and improved methods and devices for the delivery of aminoglycoside antibiotic compounds to a patient by inhalation to reduce administration costs, increase patient compliance and enhance overall effectiveness of the inhalation therapy.